Xanthene-9-methyl dialkylamino-alkanoates



United States Patent "ice 3,149,125 XANTHENE-9-METHYL DIALKYLAMINO- ALKANOATES Kurt J. Rorig, Glenview, 111., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed Nov. 27, 1961, Ser. No. 155,160 7 Claims. (Cl. 260-335) This invention relates to xanthene-9-alkyl dialkylaminoalkanoates and processes for the preparation thereof. More particularly, this invention relates to chemical compounds of the formula Alk-OC-A1k"-N wherein Alk and Alk" represent alkylene radicals and R and R" represent alkyl radicals. Among the alkylene radicals represented by Alli and Alk", especially lower alkylene radicals are preferred, which is to say bivalent, saturated, acyclic, straightor branched-chain hydrocarbon groupings of the formula wherein n represents a positive integer ordinarily less than 5. Illustrative of such radicals are methylene, ethylene, propylene, trimethylene, Z-methylpropylene, tetramethylene, etc. Likewise the alkyl radicals represented by R and R" are desirably of lower order, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertbutyl, pentyl, neopentyl, hexyl, heptyl, and like monovalent, saturated, acyclic, straightor branched chain hydrocarbon groupings of the formula wherein m represents a positive integer ordinarly less than 8.

Equivalent to the foregoing tertiary amines for present purposes are non-toxic acid addition and quaternary ammonium salts thereof, the composition of which may be delineated thus wherein Alk', Alk", R, and R" retain the meanings previously assigned; T represents hydrogen or a lower alkyl, hydroxy(lower alkyl), or lower alkenyl radical, or an aralkyl radical such as a benzyl, phenylethyl, or naphthylmethyl groupings; and Q represents an anion for example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, malate, maleate, tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or the likewhich, in combination with the cationic portion of a salt aforesaid, is neither pharmacologically nor otherwise undesirable in physiologic dosage.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. For example, the tertiary bases hereof and their acid addition salts manifest a papaverine-like capacity 3,149,125 Patented Sept. 15, 1964 to directly counteract smooth muscle spasm, whereas the corresponding quaternary ammonium salts function like tetraethylammonium bromide to block autonomic ganglionic nerve impulse transmission. These properties are to be distinguished from the spasmolytic effects of substances such as atropine, which act preponderantly at the neuro-eifector junctions of the autonomic nervous system.

Preparation of the subject compounds proceeds by heating a 9-xanthenealkanol lk-OH with an appropriate chloroalkanoyl chloride (Alk' and Alk" being defined as before) in an inert solvent such as benzene or ether, using a tertiary base such as pyridine as an acid acceptor if desired, to give a corresponding 9-xanthenealky1 chloroalkanoate which, in turn, is heated with an appropriate secondary amine (R' and R being defined as before), in an inert solvent medium such as butanone and catalyzed with sodium iodide, to give a corresponding tertiary amine of the invention. The latter reaction is carried out in a sealed vessel to the extent necessary to prevent loss by volatilization of the secondary amine in process. Conversion of the tertiary amine to its acid addition salt is accomplished by simple admixture with one equivalent of any of various inorganic and strong organic acids, theanionic portion of which conforms to Q as hereinabove defined. The quaternary ammonium compounds comprehended are deequivalent of an organic ester of the formula T and Q being limited by the meanings hereinbefore assigned and it being additionally provided that T does not represent hydrogen. Quaternization takes place in the temperature range between 25 degrees and 200 degrees centigrade, using an inert solvent such as chloroform, acetone, butanone, methanol, butanol, or the like as reaction medium. Quaternization is ordinarily completed in from 1 to 48 hours and is generally carried out in a closed system if a lower alkyl halide-such as methyl chloride-is one of the reagents. Using methyl bromide, the manufacture of quaternary salts may be smoothly eflected in butanone solution at 70 degrees centigrade, the reaction time being approximately 1 hour.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture. However the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those droxide.

EXAMPLE 1 A. 9-xanthenemethyl chloracetate.A solution of 90 parts of 9-xanthenemethanol and 57 parts of chloroacetyl chloride in 265 parts of benzene is heated to boiling at a rate such that evolution of hydrogen chloride is not unduly vigorous, and maintained at the boiling point under reflux for /2 hour. Removal of solvent by distillation and recrystallization of the residue from hexane (13.1. 60-71 affords 9-xanthenemethyl ,chloroacetate melting at 80- 84.

B. 9-xanthenemethyl diethylaminoacetate.-A solution of 58 parts of 9-xanthenemethyl chloroacetate, 33 parts of diethylamine, and 1 part of sodium iodide in 200 parts of butanone is heated at the boiling point under reflux for 12 hours, whereupon the butanone is removed by vacuum distillation and the residue taken up in 5% hydrochloric acid. The acid extract is washed with ether and then basified with aqueous concentrated sodium hy- The oil thrown down is extracted with ether, and the ether extract is dried over anhydrous sodium sulfate and stripped of solvent by distillation. The residue, upon distillation in vacuo, afiords 9-xanthenen1ethyl diethylaminoacetate boiling at 150-155 under 0.2 mm. pressure and having the formula ride.-To a solution of 16 parts of 9-xanthenemethyl diethylaminoacetate 'in 200 parts of anhydrous ether is added just sufficient hydrogen chloride to induce acidity.

Precipitation of 9-xanthenemethyl diethylaminoacetate hydrochloride occurs. The product is filtered out and dried in vacuo. .Being exceedingly hygroscopic, its melting point is indistinct under ordinary working condtions.

- D. Q-xanthenemethyl diethylaminoacetate methobromide.Approximately 14 parts of methyl bromide is introduced beneath the surface of an ice-cold solution of 32 parts of 9-xanthenemethy1 diethylaminoacetate in 200 parts of butanone. The resultant solution is let stand in a sealed vessel to warm to room temperature, during the courseof which crystalline 9-xanthenemethyl diethylarninoacetate methobromide is thrown down. When precipitation is complete, the produce is filtered off and washed with butanone. It melts at 164-167".

EXAMPLE 2 after made basic with aqueous concentrated sodium hydroxide. 7 The oil thrown down is extracted with ether. The ether extract is dried over anhydrous sodium sulfate and stripped of solvent by distillation. Vacuum distillation of the residue affords 9-xanthenemethyl diisopropylaminoaoetate boiling at 190-192" under 0.5 mm. pres- The product has the formula sure.

B. 9-xanthenemethyl dz'isopropylaminoacetate hydrochl0ride.To a solution of 8 parts of 9-xanthenemethyl diisopropylaminoacetate in 200 parts of anhydrous ether is slowly added with vigorous agitation just sufficient 2- propanolic hydrogen chloride to render the resultant mixture acid. The oil thrown down in process granules upon refrigeration of the mixture. Filtered OE and recrystallized from a mixture of ethanol and ether, this material is too hygroscopic to afiord a definitive melting point. The product thus isolated is 9-xanthenemethyl diisopropylaminoacetate hydrochloride.

C. Q-xanthenemethyl diisopropylaminoacetate methio dide.--A solution of 10 parts of 9-xanthenemethyl diisopropylarninoacetate and 6 parts of methyl iodide in 450 parts of chloroform is maintained in a sealed vessel at about 25 for two weeks. 7 Solvent is then removed-by vacuum distillation. The residual oil, upon standing in contact withether, crystallizes. The crystalline material, filtered off and recrystallized from a mixture of butanone and ether, affords 9-xanthenernethyl diisopropylaminoacetate methiodide melting at 121l24 with gas evolution.

EXAMPLE 3 A. Q-xanthenemethyl 3-chlor0pr 0pi0nate.To a solution of 53 parts of 9-vanthenemethanol and 20 parts of pyridine in 425 parts of ether at 5-10 is slowly added a solution of 32 parts of 3-chloropropionyl chloride in 71 parts of ether. The resultant mixture is allowed to warm to room temperature, then heated at the boiling point under reflux for 10 minutes. The mixture thus obtained is consecutively Washed with 200 parts of cold water, 200 parts of dilute hydrochloric acid, and twice more with 200 parts of water, whereupon it is dried over calcium sulfate and stripped of solvent by distillation. Vacuum distillation of the residue affords 9-xanthenemethyl 3-chloropropionate as a pale yellow oil boiling at 160- 163 under 0.4 mm. pressure.

B. 9-xanthenemethyl 3-dimethylamin0pr0pi0nale. Approximately 8 parts of dimethylamine is introduced beneath the surface of an ice-cold solution of 26 parts of 9-xanthenemethyl 3-chloropropionate in 40 parts of butanone. The resultant solution is let stand at about 25 in a sealed vessel for 15 hours, then heated to for 6 hours. the residual oil taken up in 250 parts of 5% hydrochloric acid. The acid solution is washed with ether and then basified with aqueous concentrated sodium hydroxide. The oil thrown down is extracted with ether, whereupon the ether extract is dried over calcium sulfate and freed of solvent by distillation. The residue, 9-xanthenemethyl 3-dimethylaminopropionate is a pale yellow oil. The product has the formula (Ill) 1 C. 9-xanthenemethyl 3-dimethylaminopropionate hy-- Butanone is removed by vacuum distillation and by the procedure there detailed, 9-xanthenernethyl 3-dimethylarninopropionate hydrochloride melting at 179- 181.

D. Q-xanthenemethyl S-dimethylaminopropionafe methiodide.Substitution of parts of 9-xanthenemethyl 3-dimethylaminopropionate for the 9-xanthenemethy1 diisopropylaminoacetate called for in Example 2C affords, by the procedure there detailed, 9-xanthenemethyl 3-dimethylaminopropionate methiodide melting at approximately l94-l95.

E. Q-xanthenemelhyl 3-dime1fhylaminopropionate methochloride.Approximately 10 parts of methyl chloride is introduced beneath the surface of a solution of 57 parts of 9-xanthenemethyl 3-dimethylaminopropionate in 750 parts of chloroform. The resultant solution is maintained in a sealed vessel at 45 for 6 hours, whereupon the chloroform is removed by distillation at reduced pressures and the residual oil taken up in approximately 200 parts of hot butanone and diluted with ether to incipient turbidity. From the turbid solution, upon cooling, 9-xanthenernethyl 3-dimethylaminopropionate methochloride precipitates which, filtered off and recrystallized from a mixture of ethanol and ether, melts at 166170. The product is hygroscopic.

EXAMPLE 4 A. 9-xai'zthenemethyl 3-dietlzylaminopropionate.Substitution or" 13 parts of diethylamine for the dimethylamine called for in Example 3B afiords, by the procedure there detailed, 9-xanthenemethyl 3-diethylaminopropionate, which is further purified by vacuum distillation. The product boils at 150l52 under 0.3 mm. pressure and has the formula I H CH2O(fiC 2C 2N( 2 5)z B. 9-xanthenemethyl 3-die2hylaminopr0pi0nate hydrochl0ride.Substitution of 8 parts of 9-xanthenemethyl 3-diethylaminopropionate for the 9-xanthenernethyl diisopropylaminoacetate called for in Example 23 afiords, by the procedure there detailed, 9-xanthenemethyl 3-diethylarninopropionate hydrochloride melting at 143- 145.

C. Q-xanthenemethyl S-diethylaminopropiomzte methi0dide.A solution of 80 parts of 9-xanthenemethyl B-diethylaminopropionate and 34 parts of methyl iodide 0 1O I H l 5 CH2 O-(fi alkylene-N (alkyl) 3 wherein the alkylene radical called for contains fewer than 5 carbon atoms and the alkyl radicals called for each contain fewer than 8 carbon atoms. 2. A compound of the formula wherein the alkyl radicals called for each contain fewer than 8 carbon atoms.

3. 9-xanthenemethyl diethylaminoacetate. 4. 9-xanthenemethy1 diisopropylaminoacetate.

5. A compound of the formula wherein the alkyl radicals called for each contain fewer than 8 carbon atoms.

6. 9-xanthenemethyl 3-dimethylaminopropionate.

7. 9-xanthenemethy13-diethy1aminopropionate.

No references cited. 

1. A COMPOUND OF THE FORMULA 